Pramipexole, the generic name of the compound (S)-2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole, is a commercial product with dopamine D-2 agonist activity. The product is marketed in dihydrochloride form for treating Parkinson's disease and schizophrenia.
Pramipexole was described for the first time in patent EP 186 087. Said patent describes the obtainment of pramipexole and analogues the key reaction of which is halogen displacement of an alpha-halo-4-N-alkylamino-cyclohexanone (the halogen is generally bromine) by sulfur from thiourea and subsequent cycling on the ketone to give the aminothiazole ring. Patent EP 207 696 describes compounds related to pramipexole and the same synthetic approach is used. The drawback of both syntheses is that the preparation of the alpha-halo-4-N-alkylamino-cyclohexanone takes place with a poor yield.
Another synthetic approach to pramipexole is described in patent application WO 02 22950. In this case, the aminothiazole ring is synthesized similar to the synthesis in patent EP 186 087, by reacting thiourea with alpha-monobromo-1,4-cyclohexanedione derivatives and then introducing the n-propylamino group by reductive amination with sodium cyanoborohydride and n-propylamine. In both processes, bromine is used as a halogenation reagent with the subsequent risk involved as it is a very reactive and extremely toxic product. Furthermore, in patent application WO 02 22950 sodium cyanoborohydride is additionally used as a reduction reagent, which have problems due to decomposition in an acid medium, with the possibility of generating cyanhydric acid, an extremely poisonous reagent.
Therefore, there are problems in the known syntheses of pramipexole that are associated to the use of certain reagents the handling of which is hazardous, in addition to the low yields in some parts of the mentioned processes. Therefore a process is needed which in part or wholly eliminates said problems but which can also be applied at an industrial scale, providing a product with a good yield and quality.